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PML tumor suppressor is regulated by HIPK2-mediated phosphorylation in response to DNA damage

E Gresko1, S Ritterhoff, J Sevilla-Perez

  • 1Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland.

Oncogene
|November 19, 2008
PubMed

Insights

Homeodomain-interacting protein kinase 2 (HIPK2) phosphorylates the promyelocytic leukemia (PML) tumor suppressor protein, impacting cell death pathways. This interaction is crucial for stabilizing PML and PML-RARalpha proteins following DNA damage.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cellular Biology

Background:

  • The promyelocytic leukemia (PML) protein is a critical tumor suppressor regulating cell proliferation and apoptosis.
  • PML is frequently aberrantly fused to retinoic acid receptor-alpha (RARalpha) in acute promyelocytic leukemia (APL).

Purpose of the Study:

  • To investigate the interaction between the tumor suppressor PML and serine/threonine kinase homeodomain-interacting protein kinase 2 (HIPK2).
  • To elucidate the role of HIPK2-mediated phosphorylation of PML in the DNA damage response and its implications for PML-RARalpha fusion proteins.

Main Methods:

  • Co-immunoprecipitation assays to demonstrate protein-protein interactions.
  • Western blotting to detect protein phosphorylation and stabilization.
  • Analysis of SUMOylation patterns in response to DNA damage and HIPK2 expression.

Main Results:

  • HIPK2 directly interacts with and phosphorylates PML at specific N-terminal sites (serines 8 and 38) early in the DNA damage response.
  • Phosphorylation of the oncogenic PML-RARalpha fusion protein by HIPK2 occurs with delayed kinetics compared to wild-type PML.
  • DNA damage or HIPK2 expression induces stabilization of both PML and PML-RARalpha proteins.
  • HIPK2-mediated phosphorylation of PML is essential for DNA damage-induced SUMOylation and for PML's ability to cooperate with HIPK2 in inducing cell death.

Conclusions:

  • HIPK2 acts as a key regulator of PML stability and function, particularly in the context of DNA damage.
  • The differential phosphorylation kinetics of PML and PML-RARalpha by HIPK2 may contribute to the distinct biological outcomes in APL.
  • Targeting the PML-HIPK2 interaction or HIPK2 activity could represent a therapeutic strategy in cancers involving PML dysregulation.

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